The investigator recently cloned a CTG expansion that causes a novel form of spinocerebellar ataxia (SCA8) and demonstrated that the repeat is transcribed in the CTG-orientation, as in myotonic dystrophy, but not the CAG-orientation, as reported for all of the other SCAs. SCA8 has the clinical features and overall pathology typical of spinocerebellar ataxia, whereas the untranslated CTG expansion responsible for this disease has only previously been seen in myotonic dystrophy. During the isolation of the SCA8 transcript we unexpectedly identified a partially overlapping mRNA containing a long open reading frame transcribed in the opposite direction, suggesting that SCA8 may be an endogenous antisense RNA whose normal function is to regulate the expression of the sense transcript. The sense transcript encodes a protein (KLHL1) highly homologous to the Drosophila KELCH protein. SCA8 is characterized by a material penetrance bias as well as a complex pattern of repeat instability that has not been observed in other triplet repeat diseases. The maternal penetrance bias is consistent with the preponderance of maternal expansions yielding alleles within the pathogenic range (-107 about250 CTGs), while paternal deletions usually result in alleles shorter than the pathogenic threshold (-100 CTGs). In some cases, maternal expansions result in very large apparently non-pathogenic alleles (250 about800 CTGs). Sperm samples from two males with very large repeats (500 and 800) underwent repair en-masse with all or nearly all of the expanded alleles undergoing massive deletions to repeat lengths at or below the pathogenic threshold (-100 CTGs). SCA8 also differs from other triplet repeat diseases in that the CTG tracts on affected alleles are often interrupted and both the overall length and the number of interruptions within the CTG tract frequently changes from one generation to the next. Their hypothesis is that SCA8 pathogenesis is mediated by transcripts containing elongated CUG repeat expansions by either affecting the expression of KLHL1 or through other toxic properties intrinsic to transcripts containing elongated CUG repeats. We propose to identify the pathogenic moiety of the SCA8 transcript by developing in vitro and transgenic models. Data obtained from SCA8 families about the effects of repeat size, sequence configuration and instability on disease penetrance will be used to refine our models. Understanding how the untranslated SCA8 CTG repeats expansion causes ataxia should help to more fully understand the pathophysiology of both ataxia and myotonic dystrophy.